A genome-wide association study identifies genetic loci associated with specific lobar brain volumes

Sven J van der Lee; Maria J Knol; Ganesh Chauhan; Claudia L Satizabal; Albert Vernon Smith; Edith Hofer; Joshua C Bis; Derrek P Hibar; Saima Hilal; Erik B van den Akker; Konstantinos Arfanakis; Manon Bernard; Lisa R Yanek; Najaf Amin; Fabrice Crivello; Josh W Cheung; Tamara B Harris; Yasaman Saba; Oscar L Lopez; Shuo Li; Jeroen van der Grond; Lei Yu; Tomas Paus; Gennady V Roshchupkin; Philippe Amouyel; Neda Jahanshad; Kent D Taylor; Qiong Yang; Rasika A Mathias; Stefan Boehringer; Bernard Mazoyer; Ken Rice; Ching Yu Cheng; Pauline Maillard; Diana van Heemst; Tien Yin Wong; Wiro J Niessen; Alexa S Beiser; Marian Beekman; Wanting Zhao; Paul A Nyquist; Christopher Chen; Lenore J Launer; Bruce M Psaty; M Kamran Ikram; Meike W Vernooij; Helena Schmidt; Zdenka Pausova; Diane M Becker; Philip L De Jager; Paul M Thompson; Cornelia M van Duijn; David A Bennett; P Eline Slagboom; Reinhold Schmidt; W T Longstreth; M Arfan Ikram; Sudha Seshadri; Stéphanie Debette; Vilmundur Gudnason; Hieab H H Adams; Charles DeCarli

doi:10.1038/s42003-019-0537-9

A genome-wide association study identifies genetic loci associated with specific lobar brain volumes

Commun Biol. 2019 Aug 2:2:285. doi: 10.1038/s42003-019-0537-9. eCollection 2019.

Authors

Sven J van der Lee¹, Maria J Knol¹, Ganesh Chauhan^{2

3}, Claudia L Satizabal^{4

5}, Albert Vernon Smith^{6

7}, Edith Hofer^{8

9}, Joshua C Bis¹⁰, Derrek P Hibar¹¹, Saima Hilal^{1

12

13

14}, Erik B van den Akker^{15

16

17}, Konstantinos Arfanakis^{18

19}, Manon Bernard²⁰, Lisa R Yanek²¹, Najaf Amin¹, Fabrice Crivello²², Josh W Cheung¹¹, Tamara B Harris²³, Yasaman Saba²⁴, Oscar L Lopez²⁵, Shuo Li²⁶, Jeroen van der Grond²⁷, Lei Yu¹⁹, Tomas Paus^{28

29}, Gennady V Roshchupkin^{1

14

30}, Philippe Amouyel³¹, Neda Jahanshad¹¹, Kent D Taylor³², Qiong Yang²⁶, Rasika A Mathias²¹, Stefan Boehringer¹⁷, Bernard Mazoyer²², Ken Rice³³, Ching Yu Cheng³⁴, Pauline Maillard³⁵, Diana van Heemst³⁶, Tien Yin Wong³⁴, Wiro J Niessen^{30

37}, Alexa S Beiser^{5

26}, Marian Beekman¹⁵, Wanting Zhao³⁴, Paul A Nyquist³⁸, Christopher Chen^{12

13}, Lenore J Launer²³, Bruce M Psaty^{10

39

40

41}, M Kamran Ikram^{1

42}, Meike W Vernooij^{1

14}, Helena Schmidt²⁴, Zdenka Pausova^{20

43}, Diane M Becker²¹, Philip L De Jager^{44

45}, Paul M Thompson¹¹, Cornelia M van Duijn¹, David A Bennett¹⁹, P Eline Slagboom¹⁵, Reinhold Schmidt⁸, W T Longstreth^{39

46}, M Arfan Ikram¹, Sudha Seshadri^{4

5}, Stéphanie Debette^{2

47}, Vilmundur Gudnason^{6

7}, Hieab H H Adams^{1

14

48}, Charles DeCarli⁴⁹

Affiliations

¹ 1Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, 3015CN the Netherlands.
² 2University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, 33000 Bordeaux, France.
³ 3Centre for Brain Research, Indian Institute of Science, Bangalore, 560012 India.
⁴ The Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78229 USA.
⁵ 5Boston University School of Medicine and the Framingham Heart Study, Boston, MA 02118 USA.
⁶ 6Icelandic Heart Association, 201 Kopavogur, Iceland.
⁷ 7Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
⁸ 8Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, 8036 Austria.
⁹ 9Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, 8036 Austria.
¹⁰ 10Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101 USA.
¹¹ 11Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90292 USA.
¹² 12Department of Pharmacology, National University of Singapore, Singapore, 117600 Singapore.
¹³ 13Memory, Aging and Cognition Center, National University Health System, Singapore, 119228 Singapore.
¹⁴ 14Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, 3015CN the Netherlands.
¹⁵ 15Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, 2333ZA the Netherlands.
¹⁶ 16Pattern Recognition & Bioinformatics, Delft University of Technology, Delft, 2628XE the Netherlands.
¹⁷ 17Department of Biomedical Data Sciences, Statistical Genetics, Leiden University Medical Center, Leiden, 2333ZA the Netherlands.
¹⁸ 18Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616 USA.
¹⁹ 19Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612 USA.
²⁰ 20The Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8 ON Canada.
²¹ 21GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205 USA.
²² 22Neurofunctional Imaging Group - Neurodegenerative Diseases Institute, UMR 5293, Team 5 - CEA - CNRS - Bordeaux University, Bordeaux, 33076 France.
²³ 23Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892 USA.
²⁴ 24Research Unit-Genetic Epidemiology, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
²⁵ 25Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260 USA.
²⁶ 26Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118 USA.
²⁷ 27Department of Radiology, Leiden University Medical Center, Leiden, 2333ZA the Netherlands.
²⁸ 28Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, M4G 1R8 Canada.
²⁹ 29Departments of Psychology and Psychiatry, University of Toronto, Toronto, M5S 1A1 Canada.
³⁰ 30Department of Medical Informatics, Erasmus MC University Medical Center, Rotterdam, 3015CN the Netherlands.
³¹ Univ. Lille, Inserm, Centre Hosp. Univ Lille, Institut Pasteur de Lille, LabEx DISTALZ-UMR1167 - RID-AGE - Risk factors and molecular determinants of aging-related, 59000 Lille, France.
³² 32Institute for Translational Genomics and Population Sciences, Department of Pediatrics at LABioMed-Harbor-UCLA Medical Center, Torrance, CA 90502 USA.
³³ 33Department of Biostatistics, University of Washington, Seattle, WA 98195 USA.
³⁴ 34Singapore Eye Research Institute, Singapore National Eye Center, Singapore, 169857 Singapore.
³⁵ 35Imaging of Dementia and Aging (IDeA) Laboratory, University of California-Davis, Davis, CA 95817 USA.
³⁶ 36Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2333ZA the Netherlands.
³⁷ 37Faculty of Applied Sciences, Delft University of Technology, Delft, 2629HZ the Netherlands.
³⁸ 38Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205 USA.
³⁹ 39Department of Epidemiology, University of Washington, Seattle, WA 98195 USA.
⁴⁰ 40Department of Health Services, University of Washington, Seattle, WA 98195 USA.
⁴¹ 41Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101 USA.
⁴² 42Department of Neurology, Erasmus MC University Medical Center, Rotterdam, 3015CN the Netherlands.
⁴³ 43Departments of Physiology and Nutritional Sciences, The Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8 Canada.
⁴⁴ 44Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY 10032 USA.
⁴⁵ 45Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142 USA.
⁴⁶ 46Department of Neurology, University of Washington, Seattle, WA 98195 USA.
⁴⁷ 47Department of Neurology, University Hospital of Bordeaux, Bordeaux, 33000 France.
⁴⁸ 48Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁴⁹ 49Department of Neurology and Center for Neuroscience, University of California at Davis, Davis, CA 95817 USA.

Abstract

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.

Keywords: Biomarkers; Genome-wide association studies; Neurology.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Frontal Lobe / diagnostic imaging
Frontal Lobe / growth & development*
Gene Expression Regulation, Developmental
Genetic Loci*
Genetic Variation*
Genome-Wide Association Study
Genotype
Heredity
Humans
Magnetic Resonance Imaging
Occipital Lobe / diagnostic imaging
Occipital Lobe / growth & development*
Organ Size / genetics
Parietal Lobe / diagnostic imaging
Parietal Lobe / growth & development*
Phenotype
Temporal Lobe / drug effects
Temporal Lobe / growth & development*
United Kingdom

Abstract

Publication types

MeSH terms

Grants and funding